Comparison of the prognostic value of measures of the tumor inflammatory cell infiltrate and tumor-associated stroma in patients with primary operable colorectal cancer

Abstract

The aim of the present study was to compare the clinical utility of two measures of the inflammatory cell infiltrate -a H&E-based assessment of the generalized inflammatory cell infiltrate (the Klintrup-M€ akinen (KM) grade), and an immunohistochemistry-based assessment of combined CD3C and CD8 C T-cell density (the "Immunoscore"), in conjunction with assessment of the tumor stroma percentage (TSP) in patients undergoing resection of stage I-III colorectal cancer (CRC). Two hundred and forty-six patients were identified from a prospectively maintained database of CRC resections in a single surgical unit. Assessment of KM grade and TSP was performed using full H&E sections. CD3C and CD8 C T-cell density was assessed on full sections and the Immunoscore calculated. KM grade and Immunoscore were strongly associated (p < 0.001). KM grade stratified cancer-specific survival (CSS) from 88% to 66% (p D 0.002) and Immunoscore from 93% to 61% (p < 0.001). Immunoscore further stratified survival of patients independent of KM grade from 94% (high KM, Im4) to 60% (low KM, Im0/1). Furthermore, TSP stratified survival of patients with a weak inflammatory cell infiltrate (low KM: from 75% to 47%; Im0/1: from 71% to 38%, both p < 0.001) but not those with a strong inflammatory infiltrate. On multivariate analysis, only Immunoscore (HR 0.44, p < 0.001) and TSP (HR 2.04, p < 0.001) were independently associated with CSS. These results suggest that the prognostic value of an immunohistochemistry-based assessment of the inflammatory cell infiltrate is superior to H&E-based assessment in patients undergoing resection of stage I-III CRC. Furthermore, assessment of the tumor-associated stroma, using TSP, further improves prediction of outcome.Abbreviations: H&E, haematoxylin and eosin; KM, Klintrup-M€ akinen; TSP, tumor stroma percentage KEYWORDS Colorectal cancer; tumor inflammatory cell infiltrate; tumor microenvironment; tumor stroma

Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non–Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors

“…High grade inflammation at the invasive margin was found to be a strong independent prognostic factor for survival in Dukes A and B colorectal carcinomas [62]. The prognostic value of the Klintrup-Mäkinen score has subsequently been validated in independent cohorts [63–67]. …”

“…The relative benefits and limitations of semi-quantitative H&E assessment compared with digital quantitation of IHC stained slides in colorectal carcinoma have begun to be addressed [65–67]. The digital image analysis software used by Galon et al was developed in-house and is not publically available for independent validation and comparison with other methodologies [76].…”

Diagnostic value of inflammatory cell infiltrates, tumor stroma percentage and disease-free survival in patients with colorectal cancer

“…The prognosis of patients is performed by staging of primary tumor and the involvement of metastases in the lymph nodes and distant organs by standard classification of the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) classification based upon the tumor-node-metastasis (TNM) (2). However, recent reports in the literature indicated that a considerable heterogeneity of the primary tumor of colon cancer requires a more detailed qualitative analysis, all of its components such as inflammatory response and connective tissue stroma (3,4).…”

Colorectal cancer subtypes: Translation to routine clinical pathology

“…The KM grade, assesses the general local inflammatory infiltrate at the invasive margin using an H&E section, and marks it on a four point score [12]. When Park and co-workers compared the two scores in 246 patients with CRC, the immunoscore stratified patients survival from 93% to 61% (HR 0.66 95% CI 0.56-0.88) and the KM grade from 88% to 66% (HR 0.44 95% CI 0.25-0.76), similar ranges to those seen for TILs [39]. Since the prognostic value of these scores was similar either approach provides a simple, effective method to subtype CMS1 tumours within routine pathology.…”

“…Parks and coworkers observed that an increase in the tumour stroma as measured by the tumour-stroma percentage (TSP) was a poor prognostic factor for CRC patients (HR 2.46 95% CI 1.56-3.89). TSP stratified 5 year patient survival from 80% (low) to 57% (high) [39]. The TSP measures the percentage of the tumour area infiltrated by stroma, with 50% being a commonly used cut off between low and high.…”